PROJECT SUMMARY Aging and hypertension are primary risk factors for the development of cerebral vascular disease (CVD), stroke, vascular cognitive impairment (VCI), and increasingly have been implicated in accelerating the progression of Alzheimer?s disease (AD). CVD is the primary etiology associated with 46% of the cases of dementia identified among the 10,713 elderly patients (69-88 years) in the Atherosclerosis Risk in Communities-Neurocognitive Study (ARIC-NCS). However, the genes and mechanisms involved are unknown. We recently discovered that sequence variants in gamma-adducin (Add3) are linked to the development of white matter hyperintensities, microhemorrhages, changes of hippocampal volume and cognitive impairments in this population. We also identified a homologous K572Q mutation in Add3 in FHH rats in which autoregulation of cerebral blood flow (CBF) is impaired. Mutations in the adducin gene family have been linked to the development of hypertension in human association studies, but the role of adducin in the regulation of cerebral vascular function and the development of CVD and cognitive dysfunction with aging and hypertension is unknown. Autoregulation is a vital homeostatic mechanism that maintains adequate CBF despite fluctuations in pressure. It protects cerebral capillaries from increases in pressure that are associated with blood-brain barrier (BBB) leakage, cerebral edema, and neurological damage. This proposal builds upon our recent findings that the myogenic response of cerebral arteries and autoregulation of CBF are impaired in FHH rats and that it was rescued by substitution of a region of chromosome 1, containing 15 genes including Add3, from a Brown Norway rat. This project will use molecular and transgenic approaches to explore whether this mutation in Add3 in FHH rats is responsible for the impaired myogenic response and autoregulation of CBF and its functional consequences in the development of CVD, VCI and AD associated phenotypes with aging and hypertension. The role of Add3 will be evaluated using novel Add3 transgenic rescue FHH rats and Zn-finger nuclease (ZFN) Add3 knockout (KO) rats that we created. We will characterize the myogenic response of cerebral arteries, autoregulation of CBF and potassium channel activity in cerebral vascular smooth muscle cells isolated from these strains. We will also compare cerebral vascular remodeling, BBB leakage, microhemorrhages, inflammation, neurodegeneration, and cognitive function with aging and hypertension. The proposed studies will have Substantial Impact and provide new information regarding the genetic susceptibility to CVD and hypertension-related dementia. They will lead to a greater recognition that genetic abnormalities, which alter cerebral vascular tone and interact with cardiovascular risk factors, accelerate disease progression, and highlight the importance of controlling blood pressure, diabetes, and obesity to delay the onset of CVD and dementia in genetically susceptible individuals.